4-39302305-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002913.5(RFC1):c.2508T>C(p.Ser836=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,610,082 control chromosomes in the GnomAD database, including 13,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.096 (875 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12178 hom.)
• Consequence: RFC1 NM_002913.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.639

Genes affected

RFC1 (HGNC:9969): (replication factor C subunit 1) This gene encodes the large subunit of replication factor C, a five subunit DNA polymerase accessory protein, which is a DNA-dependent ATPase required for eukaryotic DNA replication and repair. The large subunit acts as an activator of DNA polymerases, binds to the 3' end of primers, and promotes coordinated synthesis of both strands. It may also have a role in telomere stability. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 4-39302305-A-G is Benign according to our data. Variant chr4-39302305-A-G is described in ClinVar as [Benign]. Clinvar id is 3059082.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.639 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFC1	NM_002913.5	c.2508T>C	p.Ser836=	synonymous_variant	19/25	ENST00000349703.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFC1	ENST00000349703.7	c.2508T>C	p.Ser836=	synonymous_variant	19/25	1	NM_002913.5	P4
RFC1	ENST00000381897.5	c.2511T>C	p.Ser837=	synonymous_variant	19/25	1		A2
RFC1	ENST00000505077.1	n.440T>C		non_coding_transcript_exon_variant	4/5	4

Frequencies

GnomAD3 genomes AF: 0.0959 AC: 14582 AN: 152104 Hom.: 869 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0923

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.116 AC: 29120 AN: 251244 Hom.: 1984 AF XY: 0.118 AC XY: 16050 AN XY: 135792

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.0774

Gnomad ASJ exome AF: 0.149

Gnomad EAS exome AF: 0.206

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.128

GnomAD4 exome AF: 0.125 AC: 182047 AN: 1457860 Hom.: 12178 Cov.: 30 AF XY: 0.125 AC XY: 90366 AN XY: 725548

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.0804

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.169

Gnomad4 SAS exome AF: 0.108

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.129

GnomAD4 genome AF: 0.0959 AC: 14596 AN: 152222 Hom.: 875 Cov.: 32 AF XY: 0.0961 AC XY: 7150 AN XY: 74402

Gnomad4 AFR AF: 0.0259

Gnomad4 AMR AF: 0.0923

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.116

Alfa AF: 0.103 Hom.: 490

Bravo AF: 0.0921

EpiCase AF: 0.124

EpiControl AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

RFC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	7.9
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2066782; hg19: chr4-39303925; COSMIC: COSV62900235; COSMIC: COSV62900235;